Field of the Invention
The invention relates to heterogeneous nuclear ribonucleoprotein A2* (hnRNP A2*), a nucleic acid encoding the protein and uses thereof.
Description of the Related Art
Human chromosome ends are protected by telomeres, which are composed of TTAGGG DNA repeats and associated proteins. Telomeres shorten with each cell division because of incomplete DNA-end replication which produces a 3′ end single-stranded overhang outside the double-stranded region. Cells compensate for telomere erosion through the action of telomerase, a specialized reverse transcriptase that adds telomeric repeats to the 3′ end of the telomere.
In budding yeast, the extension of telomere is mediated by Cdc13. Cdc13 is a single-stranded telomere DNA-binding protein that associates with Est1, a protein that interacts with the RNA component of yeast telomerase. Thus, Est2 (the catalytic subunit of the yeast telomerase) is recruited to the telomere according to the following route: telomere overhang→Cdc13→Est1→Tlc1→Est2. Similarly, in Tetrahymena, Teb1 bridges the interaction between telomerase and the telomere, which promotes highly processive telomere extension by telomerase. However, in mammalian cells, the telomerase is recruited to the telomere by the Cajal body, while the mechanism(s) and factors required to promote a similar interaction between the telomere and telomerase are poorly understood.
Telomere DNA can adopt a four-stranded G-quadruplex structure that can be either intermolecular and intramolecular. Although an intermolecular G-quadruplex is an excellent substrate for ciliate telomerases, an intramolecular G-quadruplex is not. In vertebrates, intramolecular G-quadruplexes (hereinafter referred to as G-quadruplex) preferentially form at the furthest 3′ end of the telomeric DNA, rendering it inaccessible to telomerase. As a result, this structure inhibits telomere extension. Only a few proteins have been identified that can disrupt G-quadruplex. One such protein is protection of telomeres 1 (POT1), a component of the telomere shelterin complex that binds telomere overhangs with high affinity. When the 3′ end of telomere overhang and POT1 includes a tail consisting of at least 8 nucleotides, the telomere DNA can be extended by telomerase. Given the fact that POT1 takes priority to bind the minimum binding sites (MBS) of 5′-TAGGGTTAG-3′ at the 3′ end, the binding of the telomere DNA by POT1 blocks telomere ends. Despite its ability to disrupt G-quadruplex, POT1 actually inhibits telomere extension by binding to the telomere end and blocking telomerase access to the overhang. Some proteins from the hnRNP family are also able to unfold telomeric G-quadruplex. These proteins interact with telomeric ssDNA and telomerase in vitro, suggesting that they play a role in telomere biology.
hnRNPs are highly abundant proteins that play important roles in RNA metabolism. For example, hnRNP A2/B1 and A1 alone are represented by at least 107 molecules per cell, whereas a typical eukaryotic cell, such as HEK-293, has 20-50 molecules of telomerase and 92 telomere ends. In principle, these proteins should saturate both telomeres and telomerase. Therefore, it is unlikely that they could play a direct role in regulating telomere extension.